title: P450 oxidoreductase *28 (POR*28) and tacrolimus disposition in pediatric kidney transplant recipients--a pilot study.
abstract: BACKGROUND
  Both age and CYP3A5 genotype are important determinants of tacrolimus disposition in pediatric kidney transplant recipients. In a recent study in adults, POR*28 was associated with increased dosing requirements early after transplant of CYP3A5-expressing kidney transplant recipients. The authors aimed to evaluate the additional contribution of POR*28 to early tacrolimus disposition in pediatric kidney transplant recipients.
  
  
  METHODS
  Retrospective data of 43 pediatric kidney transplant recipients up to 14 days posttransplant were evaluated on tacrolimus dose and tacrolimus predose blood concentrations. Recipient POR*28 and CYP3A5 genotype were determined.
  
  
  RESULTS
  CYP3A5 expressers carrying at least 1 POR*28 allele had on average 18.3% lower tacrolimus predose concentrations and 20.2% lower concentration/dose ratios compared with CYP3A5 expressers with POR*1/*1 genotype (P = 0.002 and P = 0.001, respectively). In CYP3A5 nonexpressers, tacrolimus disposition did not significantly differ between POR genotypes.
  
  
  CONCLUSIONS
  In this small cohort of pediatric kidney transplant recipients, POR*28 genotype seems to explain part of the variability found in tacrolimus disposition, in addition to age and CYP3A5 genotype. This finding should be validated in a larger population, and it would be worthwhile to evaluate the clinical impact of this genotype.
authors.affiliation: *Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands; †Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada; ‡Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands; Departments of §Oncology; ¶Medicine; ‖Pharmacology; **Physiology; ††Biophysics, Georgetown University Medical Center, Washington, DC; and ‡‡Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: Violette M G J
authors.initials: VM
authors.lastname: Gijsen
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Offie P
authors.initials: OP
authors.lastname: Soldin
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Soldin
authors.forename: Irena
authors.initials: I
authors.lastname: Nulman
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus